Probing the regioselective C‐deuteriation of lithium enolates derived from 2‐methyl‐tetralone in the presence of substituted tertiary amines

Results are reported on the regioselective C‐deuteriation of 2‐methyl‐tetralone using a series of D‐sources and tertiary amines as potential mediators. The results presented further aid the understanding of kinetic deuteriation of both ‘base‐containing’ and ‘base‐free’ enolates. Copyright © 2006 John Wiley & Sons, Ltd.     

Investigations into the regioselective C‐deuteriation of enolates using a diisopropylammonium salt

Results are reported on the regioselective C‐deuteriation of 2‐methyl tetralone using a series of diisopropylamine derived D‐sources. The results presented further aid the understanding of kinetic deuteriation of both ‘base‐containing’ and ‘base‐free’ enolates. Copyright © 2002 John Wiley & Sons, Ltd.     

Investigations into the C‐deuteriation of aryl alkyl ketones using urea as a pro‐base in the presence of a deuterium donor

Results are reported on the regioselective C‐deuteriation of a series of enolates derived from the deprotonation of aryl alkyl ketones using dilithiated urea as the pro‐base in the presence of a suitable deuterium donor. Copyright © 2006 John Wiley & Sons, Ltd.     

Investigations into the C‐deuteriation of enol acetates derived from aryl alkyl ketones

Results are reported on the regioselective C‐deuteriation of a series of enol acetates (derived from the aryl alkyl ketones) using molecular deuterium as the D‐source and palladium‐on‐barium sulphate as the mediator. The results presented highlight potential problems associated with the deuteriation of enol acetates. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of deuterium and 15N‐labelled 2,5‐Bis[5‐amidino‐2‐pyridyl]furan and 2,5‐Bis[5‐(methoxyamidino)‐2‐pyridyl]furan

The acetate salt of 2,5‐bis[5‐amidino‐2‐pyridyl]furan‐d₂/¹⁵N₂ ( 4) was synthesized from 2,5‐bis[5‐cyano‐2‐pyridyl]furan‐d₂ ( 2 ), through the bis‐O‐acetoxyamidoxime followed by hydrogenation. Compound 2 was obtained via a Stille coupling reaction of 6‐chloronicotinonitrile with 2,5‐bis[tri‐n‐butyltin]‐furan‐d₂ ( 1 ). 2,5‐bis[5‐amidino‐2‐pyridyl)furan‐d₆ ( 10) was synthesized from 2,5‐bis[5‐cyano‐2‐pyridyl)furan‐d₆ ( 9 ) via a direct reaction with lithium bis(trimethylsilyl)amide, followed by deprotection with ethanolic HCl. ¹⁵N and/or deuterium‐labelled methoxy‐amidines 5a ‐d₂/¹⁵N₂, 5b ‐d₈, 12 , 14 ‐d₆ were prepared in good yield via direct methylation of their respective diamidoximes with either dimethylsulfate‐d₀ or dimethylsulfate‐d₆ in DMF solution and using LiOH as a base. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of deuterium‐labelled 6‐[5‐(4‐amidinophenyl)furan‐2‐yl]nicotinamidine and N‐alkoxy‐6‐{5‐[4‐(N‐alkoxyamidino)phenyl]‐ furan‐2‐yl}‐nicotinamidines

6‐[5‐(4‐Amidinophenyl)furan‐2‐yl]nicotinamidine‐d₄ ( 5 ) was synthesized from 6‐[5‐(4‐cyanophenyl)furan‐2‐yl]nicotinonitrile‐d₄ ( 3 ), through the bis‐O‐acetoxy‐amidoxime followed by hydrogenation. Compound 3 was prepared from 6‐(furan‐2‐yl)‐nicotinonitrile by a Heck coupling reaction with 4‐bromobenzonitrile‐d₄, a product of selective cyanation reaction of 1,4‐dibromobenzene‐d₄ with Cu(1)CN. Deuterium‐labelled N‐methoxy‐6‐{5‐[4‐(N‐methoxy‐amidinophenyl]‐furan‐2‐yl}‐nicotinamidines were prepared via methylation of their respective amidoximes with dimethyl sulfate‐d₆ in aqueous sodium hydroxide in good yields. Copyright © 2004 John Wiley & Sons, Ltd.     

The synthesis and structures of deuterium‐labeled 5‐substituted 1H‐tetrazoles

The synthesis and crystal structures of deuterium‐labeled 5‐substituted 1H‐tetrazoles, 5‐[²H₅]phenyl‐1H‐tetrazole (I), 5‐[²H₇]tolyl‐1H‐tetrazole (II), and 5‐[²H₇]benzyl‐1H‐tetrazole (III) are reported. All syntheses were carried out using simple, facile steps and the products were obtained in high yields. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis of deuterium labeled standards of 5‐methoxy‐N,N‐dimethyltryptamine (5‐Meo‐DMT)

The Batcho‐Leimgruber strategy was employed to synthesize 5‐[²H₃]‐methoxy‐1 H‐indole 4 from commercially available 5‐hydroxy‐2‐nitrotoluene 1 and CD₃I. Compound 4 was treated with oxalyl chloride, dimethylamine and lithium aluminum hydride to yield 5‐[²H₃]‐methoxy‐N,N‐dimethyltryptamine 6 . Copyright © 2006 John Wiley & Sons, Ltd.     

An overview of radio or stable isotope‐labeled cis‐neonicotinoid analogs

To support the metabolism and toxicology study of cis‐neonicotinoids, radio or stable isotope was introduced into different sites of the key intermediate 2‐chloro‐5‐((2‐(nitromethylene)imidazolidin‐1‐yl)methyl)pyridine (6‐Cl‐PMNI). [³H₂]‐ and [¹⁴C]‐label were successively prepared from initial materials NaB³H₄ and [¹⁴C]‐nitromethane, respectively. Similarly, [D₂]‐6‐Cl‐PMNI was prepared from NaBD₄ in four steps, with 52.6% overall isotopic yield, and dual‐labeled [D₂, ¹³C]‐target was obtained from NaBD₄ and [¹³C]‐nitromethane, affording overall isotopic yield of 42.5%. Moreover, [¹⁴C₂] was introduced from [U‐¹⁴C]‐ethylenediamine dihydrochloride in three steps, with a 58.3% overall chemical yield. Finally, typical labeled cis‐neonicotinoids paichongding and cycloxaprid were prepared and characterized. The methods were proved to have good generality in the synthesis of other cis‐neonicotinoids, and all results would be useful in metabolism studies of new cis‐neonicotinoids. Copyright © 2012 John Wiley & Sons, Ltd.     

Investigations into the C‐deuteriation of silyl enol ethers derived from aryl alkyl ketones

Results are reported on the regioselective C‐deuteriation of a series of silyl enol ethers derived from aryl alkyl ketones using deuterium (D₂) gas as the deuterium source and palladium‐on‐barium sulfate as the mediator. These results highlight the numerous reaction pathways and different product types available from simple deuteriation of substituted enol precursors. Copyright © 2006 John Wiley & Sons, Ltd.     

Synthesis of deuterium labelled 2‐bromobenzylamine by directed ortho‐metalation chemistry

Directed ortho‐metalation (DoM) strategy has been applied for the development of a short procedure for the regiospecific synthesis of [phenyl‐²H₄]‐2‐bromo‐benzylamine 6 starting from commercially available [phenyl‐²H₅]‐benzoyl chloride 1 . A strong isotope effect was observed during the ortho‐substitution. Copyright © 2005 John Wiley & Sons, Ltd.     

Synthesis of highly potent lymphocyte function‐associated antigen‐1 antagonists labeled with carbon‐14 and with stable isotopes,part 3

The drug candidates ( 2 ) and ( 3 ) are highly potent LFA‐1 inhibitors. They were efficiently prepared labeled with carbon‐14 using a palladium‐catalyzed carboxylation of an iodo‐precursor ( 5 ) and sodium formate‐¹⁴C to afford acid [¹⁴C]‐( 6 ), which was coupled via an amide bond to chiral amines ( 7 ) and ( 8 ) in 52% and 48% overall yield, respectively, and with specific activities higher than 56 mCi/mmol and radiochemical purities of 99%. For stable isotopes synthesis, the amine [²H₈]‐( 7 ) was synthesized in three steps from 2‐cyanopyridine‐²H₄ using Kulinkovich‐Szymonik aminocyclopropanation, followed by coupling to L ‐alanine‐2,3,3,3‐²H₄‐N‐t‐BOC, and then removal of the BOC‐protecting group. Amide bond formation with acid ( 6 ) gave [²H₈]‐( 2 ) in 36% overall yield. The amine [¹³C₄,¹⁵N]‐( 8 ) was obtained in two steps using L‐threonine‐¹⁴C₄,¹⁵N and then coupled to acid [¹³C]‐( 6 ) to give [¹³C₅,¹⁵N]‐( 3 ) in 56% overall yield.     

Efficient,scalable and economical preparation of tris(deuterium)‐ and 13C‐labelled N‐methyl‐N‐nitroso‐p‐toluenesulfonamide (Diazald®) and their conversion to labelled diazomethane

A method for the preparation of multi‐gramme quantities of N‐methyl‐d₃‐N‐nitroso‐p‐toluenesulfonamide (Diazald‐d₃) and N‐methyl‐¹³C‐N‐nitroso‐p‐toluenesulfonamide (Diazald‐¹³C) and their conversion to diazomethane‐d₂ and diazomethane‐¹³C, respectively, is presented. This approach uses robust and reliable chemistry, and critically, employs readily commercially available and inexpensive methanol as the label source. Several reactions of labelled diazomethane are also reported, including alkene cyclopropanation, phenol methylation and α‐diazoketone formation, as well as deuterium scrambling in the preparation of diazomethane‐d₂ and subsequent methyl esterification of benzoic acid.     

A novel five‐lipoxygenase activity protein inhibitor labeled with carbon‐14 and deuterium

2‐[4‐(3‐{(1R)‐1‐[4‐(2‐Aminopyrimidin‐5‐yl)phenyl]‐1‐cyclopropylethyl}‐1,2,4‐oxadiazol‐5‐yl)‐1H‐pyrazol‐1‐yl]‐N,N‐dimethylacetamide (1), is a novel and selective five‐lipoxygenase activity protein (FLAP) inhibitor with excellent pharmacokinetics properties. The availability of a key chiral intermediate allowed the synthesis of [¹⁴C]‐(1) in six radiochemical steps and in 47% overall radiochemical yield with a specific activity of 51 mCi/mmol using carbon‐14 zinc cyanide. 2‐Chloro‐N,N‐dimethyl‐²H₆‐acetamide was prepared and condensed with a penultimate intermediate to give [²H₆]‐(1) in very high yield and in more than 99% isotopic enrichment.     

Synthesis of 2‐d‐acrylamide

2‐d‐Acrylamide was synthesized via the 2‐step procedure starting from acrylonitrile and deuterium oxide. This procedure affords 2‐d‐acrylamide in 99.9% chemical purity and 98.4% isotopic enrichment.     

Syntheses of (R,S)‐naproxen and its 6‐O‐desmethylated metabolite labelled with 2H

Naproxen, a well‐known non‐steroidal anti‐inflammatory drug, and its 6‐O‐desmethylated metabolite have been labelled with ²H. (R,S)‐Naproxen 7 labelled with ²H was obtained in five steps using the commercially available [²H₃]iodomethane 5 as the stable labelled reagent. The demethylation of 7 using 48% HBr in 1‐butyl‐3‐methylimidazolium tetrafluoborate gave the corresponding ²H‐labelled 6‐O‐desmethylated metabolite 8. Copyright © 2008 John Wiley & Sons, Ltd.     

Ring‐chain tautomerism in 2,2‐bis(2‐thienyl)tetrahydrofurans: preparation of [butene‐2H5]‐tiagabine

A concise preparation of [butene‐²H₅]‐tiagabine hydrochloride starting from [²H₆]‐γ‐butyrolactone is described. It was necessary to ring‐open the labeled γ‐butyrolactone precursor before the addition of 2‐thienyllithium to avoid cyclisation of the intermediate to a 2,2‐bis(2‐thienyl)tetrahydrofuran. Copyright © 2010 John Wiley & Sons, Ltd.     

Synthesis of a highly potent leukocyte function‐associated antigen‐1 antagonist and its metabolite labeled with stable isotopes and carbon‐14, part 2

(S)‐2‐[(R)‐7‐(3,5‐Dichlorophenyl)‐5‐methyl‐6‐oxo‐5‐(4‐trifluoromethoxybenzyl)‐6,7‐dihydro‐5H‐imidazo[1,2‐a]imidazole‐3‐sulfonylamino]‐proprionamide (1), a potent lymphocyte function‐associated antigen‐1 antagonist and its sulfonamide metabolite (2) labeled with stable isotopes and carbon‐14 were prepared for Drug Metabolism and PharmacoKinetics and other studies. A long linear route was used to prepare [¹³C₂, ²H₃]‐(1) using [3,3,3‐²H]‐D‐alanine and [¹³C₂]‐glycine in 15 steps and 2.5% overall yield. With the availability of [¹³C₆]‐3,5‐dichloroaniline, the sulfonamide [¹³C₆]‐(2) was prepared in 12 steps and in 5.6% overall yield. For the carbon‐14 synthesis, a six‐step synthesis gave both compounds [¹⁴C]‐(1) and [¹⁴C]‐(2) from the common sulfonyl chloride intermediate [¹⁴C]‐(15) in 18% and 4% radiochemical yields and specific activities of 44 and 40.5 mCi/mmol, respectively. Copyright © 2011 John Wiley & Sons, Ltd.     

A facile synthesis of 5,5‐dideutero‐4‐dimethyl(phenyl)silyl‐6‐undecyl‐tetrahydropyran‐2‐one as a deuterium labeled synthon for (−)‐tetrahydrolipstatin and (+)‐δ‐hexadecanolide

Deuterium‐labeled biologically active compounds are gaining importance because they can be utilized as tracers or surrogate compounds to understand the mechanism of action, absorption, distribution, metabolism, and excretion. Deuterated drug molecules (heavy drugs) become novel as well as popular because of better stability and bioavailability compared with their hydrogen analogs. Labeling of organic molecules with deuterium at specific positions is thus gaining popularity. In this work, we have exploited a highly regioselective and enantioselective direct Michael addition of methyl‐d₃ alkyl ketones to dimethyl(phenyl)silylmethylene malonate that was catalyzed by (S)‐N‐(2‐pyrrolidinylmethyl)pyrrolidine/trifluoroacetic acid/ D₂O combination with high yield and isotopic purity. The 5,5‐dideutero‐4‐dimethyl(phenyl)silyl‐6‐undecyl‐tetrahydropyran‐2‐one was obtained from the adduct of methyl‐d₃ undecanyl ketone and dimethyl(phenyl)silylmethylene malonate by a silicon controlled diastereoselective ketone reduction, lactonization, and deethoxycarbonylation. The dideuterated silylated tetrahydropyran‐2‐one is the precursor for geminal ²H₂‐labeled (+)‐4‐hydroxy‐6‐undecyl‐tetrahydropyran‐2‐one, an advanced intermediate for gem‐dideutero (–)‐tetrahydrolipstatin and (+)‐δ‐hexadecanolide syntheses.     

Synthesis of deuterium‐labelled (−)‐galanthamine

The synthesis of deuterium‐labelled galanthamine is reported. 6‐[²H₃]methoxy‐N‐[²H₃]methyl‐(?)‐galanthamine was obtained in seven steps from galanthamine. The synthesis was carried out by selective O‐ and N‐demethylations. The [²H₃]‐N‐methyl and [²H₃]‐O‐methyl‐groups were introduced by selective aminoreduction and O‐methylation. Copyright © 2008 John Wiley & Sons, Ltd.